Nanohybrid urate oxidase with magnetically switchable catalytic potential for precise gout therapy

Abstract

Spatiotemporal regulation of therapeutic enzymes is desirable for enhancing the efficacy and safety of enzyme-based treatments for metabolic diseases, yet the absence of techniques capable of on-demand manipulating the in vivo catalytic activity of urate oxidase (UOx) represents a significant challenge in achieving precise gout therapy. Herein, we report a cyclic cascade nanohybrid urate oxidase (NUOx) comprised of a Fe₃O₄ nanoring core and a UOx shell, whose activity can be switched on and off on-demand using a deep-penetrated alternating magnetic field (AMF). The Fe₃O₄ nanoring under AMF exposure functions as a nanoheater to stimulate its intrinsic catalase (CAT) activity for oxygen recycling, which in turn activates UOx/CAT cascade for controlled uric acid degradation. Through the synergistic magnetothermal and UOx/CAT cyclic cascade, NUOx exhibited greatly enhanced AMF-tunability with an ON/OFF ratio as high as 7.6 and robust reversibility. This magnetically switchable NUOx enabled dynamic control of uric acid homeostasis without inducing hypouricemia and more efficient dissolution of monosodium urate crystals in vitro. In vivo experiments in a rat model of acute gout arthritis demonstrated that intra-articular administrated NUOx combined with AMF can more effectively relieve joint hypoxia, reduce uric acid levels and suppress joint inflammation, leading to a magneto-catalytic therapy with tunable therapeutic potential to enhance efficacy while minimizing potential side effects in gout treatment. These findings provide new insights into the development of nanohybrid enzymes with robust magnetic responsiveness for metabolic reprogramming and disease treatment.